Design, synthesis, and biological evaluation of dihydronaphthalene and chalcone-based anticancer agents inspired by the natural product combretastatin A-4.
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Maguire, Casey J., 1984-
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Hallmarks of tumor progression include, abnormal tumor-associated vasculature, regions of hypoxia, and overexpressed proteins. These abnormalities provide opportunities for therapeutic intervention though various targeting modalities. One such strategy takes advantage of the dependence that many solid tumors have for the rapid establishment of a vasculature network capable of supplying oxygen and nutrients to rapidly proliferating cancer cells. A class of small-molecules, referred to as vascular disrupting agents (VDAs), affect the tubulin dynamics of endothelial cells lining tumor-associated blood vessels. Tubulin depolymerization causes the endothelial cells to change shape and detach from the vessel wall leading to vessel collapse, which ultimately results in tumor necrosis. The natural product combretastatin A-4 (CA4) is widely accepted as the gold standard of VDAs and the clinical success of its corresponding water-soluble phosphate prodrug salt CA4P has inspired the development of a myriad of analogues and derivatives. Two dihydronaphthalene-based agents (KGP03 and KGP413) and their corresponding phosphate prodrug salts (KGP04 and KGP152), previously discovered by the Pinney Research Group (Baylor University), function as promising VDAs. These molecules provided impetus for our effort to devise improved synthetic routes to facilitate the preparation of sufficient material for progressive biological evaluation. The parent agents (KGP03 and KGP413) demonstrated profound inhibition of tubulin polymerization and potent cytotoxicity against human cancer cell lines (NCI-H460, SK-OV-3, and DU-145). The phosphate prodrug salts (KGP04 and KGP152), functioned as VDAs, evidenced (in collaborative studies) by disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor (KGP04), and in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc (KGP152). Tangential synthetic strategies provided access to a focused library of α-conformationally restricted chalcones and related analogues, which were evaluated (in collaborative studies) for inhibition tubulin polymerization, and cytotoxicity against human cancer cell lines (NCI-H460, SK-OV-3, and DU-145). Another targeting strategy relies on regions of hypoxia present in many solid tumors that result from poor oxygen diffusion to the tumor core. Bioreductively activatable prodrug constructs (BAPCs) utilize reductase enzyme-mediated cleavage to selectively convert a biologically inert prodrug to its corresponding biologically active parent drug in areas of pronounced tumor-associated hypoxia. Lead compounds KGP03, KGP18, and OXi8006 were evaluated as BAPCs, which incorporate bioreductive nitro-aryl triggers through an ether-linkage. The development of a scalable synthesis to KGP03 facilitated the expansion of our BAPC-library to include an additional nitrofuran series. BAPCs were evaluated (through collaboration) for inhibition of tubulin assembly, and cytotoxicity against the A549 human cancer cell line under oxic and anoxic conditions Targeting may also be achieved through recognition of over-expressed membrane receptors that are common in many forms of cancer. Antibody–drug conjugates (ADCs) consist of monoclonal antibodies (mAbs) tethered to cytotoxic drugs though synthetic linkers. ADCs exploit antibody-receptor specificity to deliver potent small-molecule anticancer agents (payloads) to cancer cells with high selectively. A series of drug-linker conjugates were prepared to investigate selectivity of cathepsin L mediated cleavage of thiosemicarbazone and dipeptide drug-linker conjugates. The synthesis of dipeptide linkers along with thiosemicarbazone intermediates has contributed to our preliminary investigation of cathepsin L selectivity. These, and other, selective targeting strategies for tumors and components of the tumor microenvironment continue to drive the discovery and development of novel anticancer agents and innovative drug delivery strategies for the improved treatment of cancer.